The overall goal of this program of research is to develop novel approaches for the prevention, treatment and modeling of Alzheimer's disease (AD). This goal will be achieved through five years of funding of 4 research projects that are supported by 4 vital cores. The approach of our drug discovery group has been and will continue to be two fold. First, we believe that the effective treatment of AD may require small molecules that easily access the brain and can be administered for years to decades. As such, we have three research projects that access small molecules, for which we have evidence of neuroprotection, effects on neuropathologies of AD, effects on cognitive decline, and that readily penetrate the brain (Project by Simpkins, Project by Meyer, Project by Koulen). Further, these compounds are expected to have little or no toxicity for reasons developed in the individual projects. Project 1 will continue a long-standing effort to discover novel compounds and mechanisms for estrogen related neuroprotection. Project 2 will continue to develop their well established program for understanding of how brain alpha7 nicotinic receptors both improve memory related behaviors and protect cells from a variety of toxic insults. Project 5 is a new research project that will identify components and mechanisms of neuroprotection mediated by N-Acylethanolamines and identify potential candidates from this group of compounds for drug development. The second strategy that we have used for drug discovery has been genetic, both for treating as well as modeling AD. We believe that ultimately, the prevention/treatment of AD may require genetic modification to replace missing or defective proteins, or reduce the production of over-expressed proteins. We have projects that use viral (Project 4) vectors for in vivo transfer of model genes, genes that produce certain aspects of AD neuropathology, and genes that are expected to prevent/treat the neuropathology of AD. The 4 supportive cores are Administrative (Core A), Vector Core (Core B), Neuroimaging Core (Core C) and Drug Synthesis Core (Core D). Collectively, this program of research will continue our successful efforts to discover novel compounds and approaches for the prevention, treatment and modeling of AD.